Trifluoromethly substituted-2,6-diphenyl-4-pyridyl carbinolamine antimalarials

ABSTRACT

A SERIES OF TRIFLUOROMETHYL SUBSTITUTED-2,6-DIPHENYL-4PYRIDYLCARBINOLAMINES IS HEREIN DISCLOSED WHICH HAS VALUE IN TREATMENT OF PALSMODIAL INFECTIONS. THE COMPOUNDS HAVE SUBSTITUTED PHENYL GROUPS AT POSITIONS 2- AND 6- ON THE PYRIDINE MOIETY, WITH THE ELECTRONEGATIVE SUBSTITUENTS (THE SAME, OR DIFFERENT) PRESENT ON THE PHENYL NUCLEI AT LEAST ONE OF WHICH IS TRIFLUOROMETHYL. THE SYNTHESES OF SUCH SERIES IS DESCRIBED, TOGETHER WITH A METHOD FOR SEPRATION OF RACEMATES OF A REPRESENTATIVE 4-PYRIDYLCARBINOLAMINE TYPE.

United States Patent 3,753,997 TRIFLUOROMETHLY SUBSTITUTED-2,6-DI- PHENYL 4 PYRIDYL CARBINOLAMINE .ANTIMALARIALS Arthur B. Ash, 1519 Chateaufont, Detroit, Mich. 48207; Peter Blumbergs, 22021 Sunset, Oak Park, Mich. 48237; Anica Markovac, 18271 Meadowood Ave., Sterling Heights, Mich. 48077; and Maurice P. La Montague, 3539 Cero Drive, Lathrup Village, Mich. 48075 No Drawing. Filed June 7, 1971, Ser. No. 150,746 Int. Cl. C07d 31/42 US. Cl. 260296 R 6 Claims ABSTRACT OF THE DISCLOSURE A series of trifiuorornethyl substituted-2,6-diphenyl-4 pyridylcarbinolamines is herein disclosed which has value in treatment of plasmodial infections. The compounds have substituted phenyl groups at positions 2- and 6- on the pyridine moiety, with the electronegative substituents (the same, or different) present on the phenyl nuclei at least one of which is trifiuoromethyl. The syntheses of such series is described, together with a method for separation of racemates of a representative 4-pyridylcarbinolamine type.

BACKGROUND OF THE INVENTION The subject invention relates to trifluoromethyl substituted-2,6-diphenyl-4-pyridinecarbinolamines having enhanced antimalarial activity, and to means for achieving the synthesis of such compounds. Specifically, the new products are pyridine-4-carbinols bearings a basic function in the alpha-position, and having the same or different substituted-phenyl groupings at positions 2- and 6- on the pyridine moiety at least one of the substituents being trifiuoromethyl. This type of compound is shown as structure I. For convenience in administration as well as stability under storage, it is preferred that subject bases be transformed into acid-addition salts with pharmaceutically acceptable inorganic or organic acids.

Prior investigations have demonstrated that certain allied alpha-di(lower alkyl) aminomethyl 2,6 diphenyl 4-pyridinecarbinols have antimalarial activity. The present invention relates to representatives which differ structurally from those known hitherto, and provide advantages in chemotherapeutic index and also in potential for avoiding unwanted side-effects such as phototoxicity.

DETAILED DISCLOSURE OF THE INVENTION The subject series of carbinolamine types is conveniently represented by the Structure I, and to pharmaceuticallyacceptable acid-addition salts thereof which also form basis for the invention. It is intended that there be included the several isomeric forms possible in Structure I, moreover.

The above (Structure I) establishes the new antimalarial agent as pyridine-4-carbinols bearing a basically-substituted unit in the alpha-position, and the same or different substituted-phenyl groupings on the pyridine ring system.

ice

This comes from definition of terms, wherein,

R=hydrogen, while R =hydrogen or (lower-alkyl) and R =(lower alkyl), the same or different from R or,

X is selected from trifluoromethyl and mono or difluoro, chloro or bromo wherein X is in the 3, 4 or 3 and 4 positions and wherein CF is in the 3 or 4 position. The term lower alkyl as used herein means 1 to 10 carbon atoms which can be straight, branched chain or cyclic with repeating methylene groups.

The patterns of worth for representatives of Structure I have been established through use of highly standardized tests in experimental mammals. The preferred mode for administering these compounds consists in use of nontoxic acid-addition salts, inclusive of those formed from (I) and acids such as hydrochloric, hydrobromic, sulfamic, sulfuric, malic, fumaric, beta-resorcylic, or pamoic acid. Said salts may be administered orally in the form of tablets, capsules, or dragees when admixed with solid excipients such as lactose, sucrose, starch, microcrystalline cellulose, magnesium stearate, or tale. The foregoing compositions are preferred means for oral administration over use of flavored syrups or tinctures containing the antimalarial drug. Under special circumstances, parenteral administration may be indicated, employing an aqueous solution of the agent or an Oleaginous formulation of it. Aqueous solutions could be prepared in water, physiological saline, Ringers solution, or the like, either with or without buffers. Oleaginous formulations may be made in natural oils (as, peanut oil or olive oil), or in benzyl benzoate, for example. The several possible isomeric forms for Structure I are to be included among the preferred antimalarials, and advantage may accrue in the choice of one or other of these.

This invention includes mode for the chemical synthesis of the series defined by Structure I. It represents an extension and amplification of art which certain of the present inventors have divulged in copending patent application of Ser. No. 784,467, filed Dec. 17, 1968, on Antimalarial Compounds and Process for the Preparation Thereof and also an application entitled 4-Pyridylcarbinolamine Antimalarials, filed on even date with the present application. Charts 1 through 3 have been used to outline the synthesis of the subject carbinolamines. As is apparent from the structure, such series occur in optically active form. A representative type, where two optical centers are present, has been separated into a pair of racemates, one of which has appreciable antimalarial activity. In another case, where only one optical center is present, the racemic pair resulting from synthesis, was subsequently separated into the dextrorotary and laevorotary forms with resulting significant antimalarial diflerences.

The course of synthesis of alpha-(dialkylaminomethyl)- 2,6-diaryl-4-pyridinecarbinols (Structure I, R =H, having R and R as lower alkyl groupings, with (Ar);, and (Ar) as substituted phenyl groups having at least one trifiuoromethyl substituent is outlined in Chart 1 and Chart 3. The requisite products have Formula 111. This method was applicable to types having (Ar) and (Ar) either the same or differing aryl functions. The intermediate oxirane could be caused to react with various primary amines (R =H; Rg=alkyl) or secondary amines (R and R each, being alkyl groupings, the same or different). Said carbinolamines (Formula III) were most satisfactorily administered in the form of acid-addition salts.

The requisite alpha- (Z-piperidyl)-2,-6-diaryl-4-pyridylcarbinols (Formula IV) were prepared from the intermediate 2, 6-diaryl-isonicotinic acids ("Formula II) in the manner outlined in Chart 2. As in the instance of the less complex carbinolamines (Chart 1), so also the products (Formula IV) of transformations given in Chart 2 were most conveniently used in the form of their acidaddition salts.

The examples hereinafter given further illustrate the preparation of 4-pyridylcarbinolamines of Formula I, but in no way limit the scope of the invention to Formulas III and IV as representative thereof. Said representations are not to be viewed as restricted to a single stereoisomeric form. All temperatures are given in degrees C.), and metric units are employed for weights and measures.

EXPERIMENTAL Synthetic paths leading to the examples have been shown in Charts 1, 2 and 3, and all are illustrative of the invention relating to 4-pyridylcarbiuolamines having Formula I. Alternative routes for acquiring certain intermediates are apparent to those skilled in the art, and certain of these are revealed in the examples. For convenience, the examples have been separated into sections to ensure clarity. Thus, the common intermediate 2,6-diaryl isonicotinic acids (Formula II) have been illustrated in Examples 1 through 6. Examples 7 through 27 are illustrative of the modes for synthesis of the carbinolamines of Formula III, and Example 27 relates to compound of Formula IV.

(A) TRIFIJUOROMETHYL SUBSTITUTED-2,6- DIPHENYL IS'ONICOTINIC ACIDS Example 1.2,6-bis (4-trifluorornethylphenyl) isonicotinic acid (1) 4-trifiuoromethylphenacyl bromide.To a solution of 4-trifluoromethylacetophenone (25 g., 0.13 mole) in chloroform (100 ml.) was added a solution of bromine (10.5 g., 0.13 mole) in chloroform (40 ml.). The reaction mixture was stirred at room temperature for 15 min. The chloroform solution was washed with. Water (X4), dried (NagSO and concentrated. The crude bromomethyl ketone was recrystallized from petroleum ether (B.P. 30-60) to yield the title compound (29.3 g., 83%), M.P. 54-56".

Analysis.-Calcd for C H OF Br (percent): C, 40.48; H, 2.27; F, 21.34. Found (percent): C, 40.47; H, 2.33; F, 21.08.

(2) N (4 trifluoromethylphenacyl)pyridinium bromide.A solution of the above bromoketone (28.3 g., 0.16 mole) in ethanol (70 ml.) containing pyridine (10 ml.) was refluxed for min. Ether was added to the cooled solution until turbid and the solution was allowed to stand overnight. Filtration aflorded 32 g. (60%) of the title pyridinium salt, M.P. 219-221 (dec.).

Analysis.Calcd for C H NOF Br (percent): C, 48.58; H, 3.20; N, 4.05; F, 16.47. Found (percent): C, 48.59; H, 3.36; N, 4.28; F, 16.21.

(3) 3-(4-trifluoromethylbenzoyl)acrylic acid-Freshly fused zinc chloride (82 g., 0.6 mole) was dissolved in dry ether (400 ml.) and added dropwise to the Grignard reagent prepared from p-bromobenzotrifiuoride (112.5 g., 0.5 mole) and magnesium (12.2 g., 0.5 g. atom) in ether (600 ml.). To the above suspension, maleic anhydride (44 g., 0.45 mole) in ethereal solution (ca. 400 ml. of ether) was added over min., with stirring and refluxing. Refluxing was continued for another 2 hr. The reaction mixture was cooled and acidified with 10% hydrochloric acid. The ethereal solution was separated, dried (magnesium sulfate) and the solvent evaporated. The dark residue was recrystallized several times from benzene until a sharp melting product was obtained, yield 24.5 g. (21%), M.P. 149-151.

Analysis.-Calcd for C11H703'F3 (percent): C, 54.11; H, 2.89; F, 23.34. Found (percent): C, 54.14; H, 3.06; F, 23.60.

An alternative, improved method of preparation of 3- (4-trifluoromethylbenzoyl)-acrylic acid is as follows. 4-

trifluoromethylacetophenone (376 g., 2 mol) and glyoxylic acid (376 g.) were heated at 79-80" for 8 hr. The reaction mixture was poured in 4 l. of water containing 38 ml. of concentrated hydrochloric acid with stirring. The mixture was extracted with ether (3 l. 1; 1.5 l. 1). The ether extract was Washed with water and the ether was removed under reduced pressure. The residue was azeotroped with chloroform (1. 1.), then stirred with petroleum ether (2.8 1., B.P. 30-60"). The mixture was filtered and the solid was Washed with petroleum ether. The solid was stirred with hot chloroform (600 ml.), cooled and filtered to yield 141 g. of 2-hydroxy-3-(4-trifluoromethylbenzoyl)propionic acid, 118-119.5 C. The petroleum ether filtrate and washings were combined and the solvent was removed under reduced pressure to yield 205 g. of unreacted 4-trifiuoromethylacetophenone. The yield of hydroxyacid, based on recovered starting mate rial, was 59%. The hydroxyacid (262 g.) was heated in an oil bath at 155-160 for 40 min. to yield crude 4- trifiuoromethylbenzoylacrylic acid. The crude product was used as such in the next reaction.

(4) 2,6-bis(4-trifluoromethylphenyl)isonicotinic acid. To a solution of 4.8 g. (0.02 mole) of 3-(4-trifiuoromethylbenzoyl)acrylic acid in 50 ml. of methanol, there was added 7.0 g. (0.02 mole) of N-(4-trifluoromethylphenacyl)pyridiniurn bromide and 16 g. of ammonium acetate. The mixture was refluxed for 6 hr. Alternatively, the addition of acetic acid proved beneficial and the reflux time was reduced to 4 hr. by this variation. The solvent was removed in vacuo and the residue so obtained was treated with 20 ml. of hot 50% acetic acid, stirred for some while and cooled. The product was collected by filtration, washed with water, dried and then recrystallized from benzene. There was thus obtained 6.6 g. of the desired isonicotinic acid type, M.P. 285-286".

Analysis.Calcd for C H F NO (percent): C, 58.40; H, 2.70; N, 3.41. Found (percent): C, 58.56; H, 2.85; N, 3.50.

Example 2.2- (4-chloropheny1)-6- (4-trifluoromethylphenyl)isonicotinic acid The procedure described in Example 1 was employed for the interaction of N-(4-trifluoromethylphenacyl)- pyridinium bromide, 3-(4-chlorobenzoyl)acrylic acid, and ammonium acetate in methanol. The requisite product was obtained in 69% yield. The pure compound, obtained by crystallization from propanol-2, had M.P. 269-271".

Analysis.CalCd for C H NO CIF (percent): C, 60.41; H, 2.94; N, 3.71; F, 15.09. Found (percent): C, 60.13; H, 3.20; N, 3.52; F, 15.10.

Example 3 .2- (4-bromophenyl) -6- (4-trifluoromethylphenyl)isonicotinic acid The method given in Example 1 was followed. 3-(4- bromobenzoyDacrylic acid, N (4-trifiuoromethylphenacyl)pyridinium bromide and ammonium acetate were refluxed in methanol solvent for five hours. After workup, the product crystallized from acetic acid to give a 60% yield of the title isonicotinic acid, M.P. 280-283 Analysis.-Calcd for C I-I NO BrF (percent): C, 54.05; H, 2.63; N, 3.32; F, 13.50. Found (percent): C, 53.85; H, 2.76; N, 3.49; F, 13.25.

Example 4.2- 3,4-dichlorophenyl) -6- 3-triflu0romethylphenyl)isonicotinic acid (1) 3 trifluoromethylphenacyl bromide.--3-trifiuoromethylacetophenone (18.8 g.) was brominated (16 g. of bromine) in 140 ml. of chloroform as described for Example 6. After the usual workup (cf. Example 1), there was obtained 21 g. (79% yield) of colorless oil which was used directly without purification.

(2) N (3 trifluoromethylphenacyl)pyridinium bro rnrde.'Ihe requisite phenacyl bromide and pyridine were interacted in ethanol solution as described in Example 1. The crude quaternary salt was recrystallized from ethanol to give of product, M.P. 248-249.

AnaZysis.Calcd for C H BrFNO (percent): C, 48.57; H, 3.20; N, 4.05. Found (percent): C, 48.49; H, 3.49; N, 3.96.

(3 2- 3,4-dichlorophenyl) -6- (3-trifluoromethylphenyl) isonicotinic acid.-The foregoing quaternary ammonium salt was caused to react with 3-(3,4-dichlorobenzoyl) acrylic acid in the manner described in Example 1 to yield 80% of the title isonicotinic acid, M.P. 239-240, after crystallization from ethanol.

Analysis.-Calcd for C H Cl F O N (percent): C, 55.37; H, 2.43; N, 3.40. Found (percent): 55.34; H, 2.63; N, 3.37.

Example 5.2- (3 ,4-dichlorophenyl -6- (4-trifluoromethylphenyl)isonicotinic acid The intermediate quaternary ammonium salt from Example 1 was caused to react with 3-(3,4-dichlorobenzoyl)acrylic acid after the manner described in Example 1. A 79% yield of product was obtained with M.P. 288- 290, after crystallization from ethanol.

Analysis.Calcd for C H Cl F NO- (percent): C,

55.37; H, 2.43; N, 3.40. Found (percent): C, 55.44; H, 2.63; N, 3.39.

Example 6.-2,6-bis(3-trifluoromethylphenyl) isonicotinic acid (1) 3 (3 trifluoromethylbenzoyl)acrylic acid-The title compound was prepared from 3-trifluoromethylacetophenone (20 g.) and glyoxylic acid hydrate (20 g., 80% purity) using alternative procedure described for Example 1. The crude product was a mixture (8.5 g.) of hydroxy and acrylic acid (M.P. 85-115) and was used for the next step without purification.

(2) N (3 trifluoromethylphenacyl)pyridinium bromideThe title compound was prepared from a-bIOInO- m-trifiuoromethylacetophenone (13.5 g.), pyridine (20 ml.) and ethanol (20 ml.) using the procedure described in Example 1. The product was recrystallized from ethanol and gave 14.6 g. (85%) of material, M.P. 248-249.

Analysis.Calcd for C I-I BrF NO (percent): C, 48.57; H, 3.20; N, 4.05. Found (percent): 48.49; H, 3.49, N, 3.96.

(3) 2,6-bis (3-trifluoromethylphenyl) isonicotinic acid.-- The foregoing mixture of hydroxy and acrylic acids (8.5 g.), n-(3-trifluoromethylphenacyl)pyridinium bromide (11 g.) ammonium acetate (20 g.), and acetic acid (10 ml.) in methanol (100 ml.) were refluxed for 8 hours. The

solution was evaporated to dryness and the residue was treated with hot acetic acid (30 ml.) After stirring and cooling, the dark product was separated and crystallized from benzene (x2). The yield was 6.8 g. (51%), M.P. 219-220".

Analy'sis-Calcd for C H F NO (percent): C, 58.40; H, 2.70. Found (percent): C, 58.62; H, 2.78.

(B) TARGET COMPOUNDS Example 7.-Alpha (n-butylaminomethyl) -2,6-bis (4- trifiuoromethylphenyl) -4-pyridinecarbinol (1) Diazomethyl 2,6 bis(4-trifluoromethylphenyl)-4- pyridyl ketone-The intermediate 2,6-bis(4-trifluoromethylphenyl)isonicotinic acid (5 g.) from Example 1 was dissolved in thionyl chloride (50 ml.) and refluxed for 3 hours. The solution Was concentrated and the residue was suspended in benzene. The solvent was evaporated and the crude acid chloride was dissolved in dichloromethane (50 ml.) and added to a solution of diazomethane (ca. 5 g.) in ether (300 ml.) at 0. The reaction mixture was refrigerated overnight. The excess of diazomethane and ether was removed under reduced pressure. The crystalline diazoketone was suspended in a mixture of ether-petroleum ether. The resulting precipitate was separated (4.2 g., 80%, M.P. 152-165 and used directly in the next step. A sample for analysis was purified by crystallization from ether-petroleum ether, M.P. 165-166 (dec).

Analysis.Calcd for C H F N O (percent): C, 57.91; H, 2.55; N, 9.65. Found (percent): C, 57.81; H 2.59; N, 9.80.

(2) Bromomethyl 2,6 di-p-trifluoromethylphenyl-4- pyridyl ketone-The above diazoketone (4 g.) was added in several portions to a mixture of 48% hydrobromic acid (10 ml.) in acetic acid ml.). The solution was stirred at room temperature for 1 hr. and diluted with cold water. The resulting precipitate was suspended in dilute sodium carbonate, filtered, washed with water and dried. The crude product was recrystallized from ethanol, M.P. 153- 154, yield 3.5 g. (77%).

Analysis.Calcd for C H F BrNO (percent): C, 51.66; H, 2.48; N, 2.87. Found (percent): C, 51.88; H, 2.48; N, 3.00.

(3) Alpha (n-butylaminomethyl)-2,6-bis(4-trifluoromethylphenyl)-4-pyridinemethanoL-Epoxide: A solution of sodium borohydride mg.) in water (5 ml.) was added to a solution of the above bromoketone (1.7 'g.) in hot ethanol (50 ml.). The solution was stirred at room temperature for 2 hr. Part of the ethanol was evaporated and the excess of borohydride was destroyed with 5% hydrochloric acid. The pH of the mixture was adjusted to 7 with aqueous sodium bicarbonate. The product was extracted with ether. The extract was washed with Water, dried (K CO and the ether was evaporated to leave crude epoxide (1.2 g., 82%) which was used without further treatment.

Carbinolamine hydrochloride: The above crude epoxide (1.2 g.) was dissolved in ethanol (50 ml.), mono-n-butylamine (5 ml.) added and the solution refluxed for 18 hr. The reaction mixture was evaporated to dryness, the residue dissolved in ether (ca. 600 ml.), washer with water, dried (K 00 and concentrated (to ca. 10 ml.). After cooling, the colorless precipitate was separated (700 mg.), dissolved in hot ethanol and converted to the hydrochloride salt was separated, washed with water and recrystallized from a mixture of ethanol and ether. The yield was 700 mg. (40%), M.P. 253-255.

Analysis.-Calcd for C H ClF N O (percent): C, 57.86; H, 4.86; N, 5.40. Found (percent): C, 57.56, H, 4.80; N, 5.31.

(4) Alternatively, the 2,6-bis-(4-trifluoromethylphenyl) isonicotinic acid may be converted to the target antimalarial compound, alpha (n-butylaminomethyl-2,6-bis- (4-trifluoromethylpheny1)-4-pyridinecarbinol, by an alternative procedure which avoids the use of diazomethane, a hazardous reagent not suitable for large scale work. The sequence is shown in Chart 3. The isonicotinic acid from Example 1 was refluxed in ethanol containing sulfuric acid to yield the ethyl ester M.P. 124.5-125.5, in 92%, yield. This is structure I of Chart 3. This is interacted with ethyl acetate in the presence of one equivalent of sodium ethoxide to obtain ethyl 2,6-bis-(4 trifluoromethylphenyl)isonicotinoylacetate, M.P. 137-138, in 95% yield. This is structure II of Chart 3. This was hydrolyzed and decarboxylated by refluxing the ketoester in a mixture of hydrochloric acid and acetic acid to form methyl 2,6-bis(4-trifluoromethylphenyl)-4-pyridyl ketone, M.P. 139-1405", in 97% yield. This is structure III of Chart 3.

The foregoing ketone was brominated in acetic acid at 80-90 over a 30 min. period. The reaction mixture was cooled, poured into water and extracted with chloroform. The chloroform solution was washed with sodium bicarbonate and water and dried. The solution was concentrated and brornomethyl 2,6-bis-(4-trifluoromethylplienyl)-4 pyridyl ketone, M.P. 152-154, identical in all respects with the compound reported above, was isolated in 84% yield. This is structure IV of Chart 3. The procedure to convert the bromoketone, to the antimalarial compound, alpha-(n-butylaminomethyl)-2,6-bis-(4 trifluoromethylphenyl)-4-pyridinecarbinol, is the same as that reported above.

Example 8.-Alpha-(n-pentylaminomethyl) -2,6-bis- (4-trifiuoromethylphenyl)-4-pyridinecarbinol The intermediate expoxide from Example 7 in ethanol solution was treated with n-pentylamine as described in Example 7. The resulting hydrochloride salt isolated was recrystallized from acetonitrile, M.P. 225227, in 75% yield.

Analysis.-Calcd for C H N F ClON (percent): C, 58.58; H, 5.11; N, 5.25; Cl, 6.65. Found (percent): C, 58.51; H, 5.31; N, 5.40; CI, 6.95.

Example 9.-Alpha-(n-hexylaminomethyl)-2,6-bis- (4-trifiuoromethylphenyl) -4-pyridinecarbinol The intermediate epoxide described in Example 7 was treated with n-hexylamine as described in Example 7. The title compound was isolated in the form of its hydrochloride salt, M.P. 208-209", in a yield of 75%; following crystallization from acetonitrile.

Analysis.Calcd for C H N F ClO (percent): C, 59.27; H, 5.36; N, 5.12; CI, 6.48. Found (percent): C, 59.00; H, 5.65; N, 5.22; Cl, 6.75.

Example 10.-Alphan-heptylaminomethyl) -2,6-bis- (4-trifluoromethylphenyl -4-pyridinecarbinol The intermediate epoxide from Example 7 was treated with n-heptylarnine as described, in Example 7. A 71% yield of hydrochloride of the title compound, M.P. 198- 199 was obtained, following crystallization of the crude material from acetonitrile.

Analysis.-Calcd for C ,,H N F ClO (percent): C, 59.94; H, 5.57; N, 4.99; Cl, 6.32. Found (percent): C, 60.01; H, 5.77; N, 5.08; Cl, 6.54.

Example 1 1.Alpha-(n-octylaminomethyl -2,6-bis- (4-trifluoromethylphenyl) -4pyridinecarbinol The intermediate epoxide from Example 7 was caused to react with n-octylamine in ethanol solution after the procedure described in Example 7.

The hydrochloride was isolated in 75% yield, M.P. 185- 186 (after crystallization from acetonitrile).

Analysis.-Calcd for C H N F Cl (percent): C, 60.57; H, 5.78; N, 4.87; Cl, 6.17. Found (percent): C, 60.07; H, 6.04; N, 4.90; CI, 6.31.

Example 12.Alpha-(cyclobutylaminomethyl) -2,6-bis- (4-trifluoromethylph enyl -4-pyridinecarbinol A solution of the epoxide (0.9 g.) from Example 7, monocyclobutylamine (8 ml.) and ethanol (20 ml.) was refluxed for 18 hrs. The solution was evaporated to dryness. The solid free base was suspended in petroleum ether (20 ml.) and separated. The solid was then dissolved in ethanol (5 ml.) and acidified with hydrochloric acid. The solution was diluted with water (ca. 10 ml.) and the hydrochloride salt was filtered. The salt was recrystallized from acetonitrile to give 750 mg. (69%) of the product, M.P. '265-267.

Analysis.-Calcd for C H ClF N O (percent): C, 58.33; H, 4.76; N, 5.63. Found (percent): C, 58.09; H, 4.49; N, 5.42.

Example 13 .--Alpha- (4-heptylaminomethyl) -2,6-bis- (4-trifluoromethylphenyl -4-pyridinecarbinol The above compound was prepared from epoxide (0.9 g.) from Example 7 and 4-heptylamine (10 ml.) using the procedure described for Example 12. The yield was 70%, M.P. 202-204 (acetonitrile), of the hydrochloric salt.

Analysis.Calcd for C H ClFgNO (percent): C, 59.94; H, 5.57; N, 4.99. Found (percent): C, 60.22; H, 5.87; N, 5.12.

Example 14.Alpha-(ethylaminomethyl)-2,6-bis- 4-trifiuoromethylphenyl) -4-pyridinecarbinol The title compound was prepared from the epoxide (600 mg.) from Example 7 and ethylamine (8 ml.) using 8 the procedure in Example 12. The yield of hydrochloride salt was 650 mg. (85%), M.P. 275276 (ethanol).

Analysis.Calcd for c H ClF N O (percent): C, 56.27; H, 4.31; N, 5.71. Found (percent): C, 56.46; H, 4.49; N, 5.51.

Example l5.Alpha-(2-butylaminomethyl)-2,6-bis- 4-trifiuoromethylphenyl -4-pyridinecarbinol The title compound was prepared from the epoxide (600 mg.) from Example 7 and sec.-butylamine (8 ml.) using the standard procedure described in Example 12. The yield of hydrochloride salt was M.P. 242-245 (ethanolether).

Analysis.-Calcd for C H ClF N O (percent): C, 57.68; H, 4.86; N, 5.40. Found (percent): C, 57.68; H, 5.13; N, 5.61.

Example l6.-Alpha-( 1'-propylaminomethy1) -2,6-bis- 4trifiuoromethylphenyl) -4-pyridinecarbinol The title compound was prepared from the epoxide (600 mg.) from Example 7 and propylarnine (8 ml.) using the procedure described in Example 12. The yield of hydrochloride salt was M.P. 267269 (ethanolacetonitrile) Analysis.-Calcd for C .,H ClF N O (percent): C, 57.09; H, 4.59; N, 5.55. Found (percent): C, 56.89; H, 4.87; N, 5.73.

Example 17.Alpha- (cyclohexylaminomethyl -2,6-bis- 4-trifiuoromethylphenyl -4-pyridinecarbinol The title compound was prepared from the epoxide (1 g.) from Example 7 and cyclohexylamine (10 ml.) using the procedure described in Example 12. The product salt was crystallized from ethanol to give 700 mg. (62%) of colorless crystals, M.P. 266468".

Analysis.-Calcd for C H ClF N 0 (percent): C, 59.50; H, 4.99; N, 5.14. Found (percent): C, 59.21; H, 4.92; N, 5.27.

Example 18.-Alpha-(di-n-butylaminomethyl)-2,6-bis- (4-trifiuoromethylphenyl -4-pyridinecarbinol The epoxide from Example 7 (2.3 g.) was dissolved in ethanol ml.). Di-n-butylamine (10 ml.) was added and the solution was refluxed for 15 hr. The reaction mixture was evaporated to dryness. The residue was dissolved in a small amount of ethanol and the solution was acidified with 10% hydrochloric acid. Crystalline title compound separated after standing at room temperature for several hours. The product was separated, washed with water, suspended in ether (to remove any expoxide), separated again and dried. The product was crystallized from a mixture of ethanol-Water, yield 1.7 g. (52%), M.P. 233-235 Analysis.-Calcd for C H ClF N O (percent): C, 60.57; H, 5.78; N, 4.87; Cl, 6.17. Found (percent). C, 60.63; H, 5.78; N, 4.83; Cl, 6.31.

The above alpha-(di-n-butylaminomethyl)-2,6-bis-(4 trifluoromethylphenyl)-4-pyridinecarbinol was resolved into its two optical antipodes in a conventional manner by conversion of the compound in to the L(d)-tartrate salt. By fractional crystallization, there was obtained salts rich in dextrorotatory and laevorotory antipodes. The anti podes were liberated from the L(d)-tartarate salts and converted back into the hydrochloride salts. As determined on a polarimeter, the rotations for the two antipodes as hydrochloride salts were [u] +10.75, C. 2.1 ethanol and [u] 10.68, C. 1.76 ethanol. The two antipodes melted at 239-240 and 236-237, respectively. The antimalarial activity of the two antipodes was different, the activity of each antipode was significantly different than that of the original racemic mixture.

An o-succinoyl derivative of the title pyridinecarbinol was prepared. The hydrochloride salt was first converted to the free base by treatment with sodium hydroxide.

The free base (1 g.) was dissolved in 50 ml. of anhydrous acetone. To this solution was added 210 mg. of succinic anhydride, then the solution was refluxed for 1 hour. Following evaporation of the solvent, the residue was suspended in cold water, then acidified to pH 4 with dilute hydrochloric acid. Following cooling, a crystalline solid separated, and was crystallized from propanol-2. An 85% yield (990 mg.) of the O-succinoyl derivative was obtained in the form of its hydrochloride salt. This compound melted 176-178.

Analysis.-Calcd for C H N ClF O (percent): C, 58.71; H, 5.52; N, 4.15. Found (percent): C, 58.68; H, 5.80; N, 4.26.

Example 19.Alpha-(di-n-pentylaminomethyl)-2,6-bis- (4-trifluoromethylphenyl -4-pyridinecarbinol The requisite epoxide (Example 7) and di-n-pentylamine were caused to interact in ethanol solution after the manner described in Example 18. The hydrochloride salt was formed, and then crystallized from ethanol-water. A yield of about 53% resulted. The compound melted 225-228.

Analysis.-Calcd for C H ClF N O (percent): C, 61.73; H, 6.18; N, 4.65. Found (percent): C, 61.57; H, 6.19; N, 4.72.

Example 20.Alpha-(di-4-heptylaminomethyl)-2,6-bis (4- trifluoromethylphenyl)-pyridinecarbinol hydrochloride The title compound was prepared from the corresponding epoxide 1.5 g.) from Example 7 and 4-dil1eptylamine (10 ml.) in ethanol (50 ml.) using the procedure in Example 18. The product weighted 650 mg., M.P. 211-213, after crystallization from acetonitrile. The yield was 650 mg, M.P. 211-213.

Analysis.Calcd for C H ClF N O (percent): C, 63.77; H, 6.88; N, 4.28. Found (percent): C, 63.93; H, 7.06; N, 4.30.

Example 21.Alpha-(di-n-butylaminomethyl) 2 (4- chlorophenyl) 6 (4 trifluoromethylphenyl) 4- pyridinecarbinol (1) Bromomethyl 2 (4-chlorophenyl)-6-(4-trifluoromethylphenyl)-4pyridyl ketone.The intermediate isonicotinic acid from Example 2 was converted into the acid chloride, which was then used in crude form for conversion into the diazomethyl ketone, also used without purification. The diazoketone and hydrobromic acid were caused to react in the presence of chloroform to obtain a 64% yield of the title bromomethyl ketone. This, following recrystallization from propanol-2, was obtained in 64% yield, M.P. 124-127 (2) Alpha-(di-n-butylaminomethyl) 2 (4-chlorophenyl) 6 (4 trifiuoromethylphenyl) 4 pyridinecarbinol.In the usual manner, the foregoing bromo methyl ketone was converted into the epoxide and treated with di-n-butylamine and gave a 34% yield of the hydrochloride of the requisite carbinolamine, M.P. 229-231, following crystallization from propanol-2.

Analysis.-Calcd for C H Cl F N O (percent): C, 62.11; H, 6.14; N, 5.17; CI, 13.10; F, 10.53. Found (percent): C, 61.99; H, 6.39; N, 5.26; Cl, 13.15; F, 10.59.

Example 22.Alpha- (n-butylaminomethyl) -2- (4-bromophenyl) -6-(4-trifluoromethylphenyl -4-pyridinecarbinol (1) Bromomethyl 2 (4-bromophenyl)-6-(trifluoromethylphenyl)-4-pyridyl ketone.The required intermediate isonicotinic acid from Example 3 was converted into its acid chloride, which melted at 139-141 following crystallization from benzene. The yield was 81%. By analysis, the compound contained 12.72% fluorine vs. 12.83% calculated. This acid chloride was interacted with diazomethane and then reacted with hydrobromic acid. There resulted thereby a 68% yield of the required bromomethyl ketone of M.P. 136-138 (from propanol- 2).

Analysis.-Calcd for C H Br F NO (percent): C, 48.05; H, 2.58; N, 2.80; F, 11.40. Found (percent): C, 48.13; H, 2.69; N, 3.00; F, 11.68.

(2) Alpha-(n-butylaminomethyl) 2 (4 bromophenyl) 6 (4 trifluoromethylphenyl) 4 pyridinecarbinol.The foregoing bromoketone was reduced with sodium borohydride in ethylene glycol monoethyl ether, to obtain the crude, intermediate epoxide which was interacted with n-butylamine in ethanol solution. The free base was obtained as a nicely crystalline solid from propanol-2 and melted 157-1585". The yield was 49%.

Analysis.Calcd for C H N BrF O (percent): C, 58.43; H, 4.90; N, 5.68; F, 11.55. Found (percent): C, 58.27; H, 4.85; N, 5.51; F, 11.22.

Example 23.Alpha-(di-n-butylaminomethyl) 2 (4- bromophenyl) 6 (4 trifiuoromethylphenyl) 4- pyridinecarbinol The crude epoxide obtained according to Example 22 was interacted with di-n-butylamine in ethanol solution to obtain a crude base, which was transformed into its hydrochloride salt. This salt was obtained in 40% yield, and melted 229-231" (crystallization effected from propanol-Z) Analysis.-Calcd for C H BrClF NO (percent): C, 57.39; H, 5.68; N, 4.78, F, 9.73. Found (percent): C, 57.16; H, 5.93; N, 4.85; F, 10.04.

Example 24.-Alpha-(di-n-butylaminomethyl) 2 (3,4-

dichlorophenyl) 6 (3 trifiuoromethylphenyl) 4- pyridinecarbinol The intermediate isonicotinic acid derivative prepared according to Example 4 was converted to crude acid chloride which was converted in turn to the diazomethyl ketone by interaction with diazomethane. The crude diazomethyl ketone was obtained in 82% yield. The bromomethyl ketone was obtained in 89% yield from the diazomethyl ketone by interaction with hydrobromic acid. Reduction of the bromomethyl ketone with sodium borohydride in the usual way gave the intermediate epoxide of adequate purity for direct conversion into the required compound. The yield so obtained was 35%. The hydrochloride was crystallized from propanol-Z, and then melted 178-179.

Example 25.-Alpha-(di-n-butylaminomethyl)-2-(3,4-dichlorophenyl) 6-(4-trifluoromethylphenyl)-4-pyridinecarbinol The requisite isonicontinic acid starting material was obtained after the procedure of Example 5, then converted successively, into the acid chloride, the diazomethyl ketone, and the bromoethyl ketone, and thence into the epoxide for interaction with di-n-butylamine. The yields in the first several steps were inexcess of however, the conversion of the bromoketone into the finished product was about 40%. The hydrochloride of the desired compound melted 208-210 following crystallization from acetonitrile and water.

Analysis.-Calcd for C H Cl F N O (percent): C, 58.39; H, 5.60; N, 4.86. Found (percent): C, 58.18; H, 5.80; N, 4.72.

Example 26.Alpha-(n-butylaminomethyl) -2,6-bis-(3- .trifiuoromethylphenyl 4-pyridinecarbinol (l) Diazomethyl 2,6 bis-(3-trifiuoromethylphenyl)- 4-pyridyl ketone.The isonicotinic acid (4.5 g.) from Example 6 was dissolved in thionyl chloride (50 ml.) and the mixture was refluxed for 3 hours. The solution was concentrated. The residue was suspended in benzene and the solvent was evaporated. The crude acid chloride was dissolved in dichloromethane (50 ml.) and added to a solution of diazomethane (5 g.) in ether (300 ml.) at 0. After refrigeration overnight, the solvent and the excess of diazomethane were evaporated. The crude diazoketone 1 1 (4.2 g.) solidified at 6, but was liquid (oil) at room temperature. It was used for the next step without purification.

(2) Bromomethyl 2,6-bis(3-trifiuoromethylphenyl)-4- pyridyl ketone.The above diazoketone (4.2 g.) was dissolved in dichloromethane (50 ml.) and added to a mixture of 48% hydrobromic acid (10 ml), acetic acid (20 ml.) and dichloromethane (100 ml.). The solution was stirred at room temperature for one hour and diluted with cold water. The solvent layer was separated. The water layer was extracted with more dichloromethane (100 ml.) and the combined extracts were washed with dilute sodium bicarbonate solution. After drying (K CO the solvent was evaporated and the semi-solid residue was crystallized from ethanol. The yield was 2.6 g. (56%), M.P. 75-77.

Analysis.-Calcd for c H F BrNO (percent): C, 51.66; H, 2.48; N, 2.87. Found (percent): C, 51.86; H, 2.70; N, 3.05.

(3) Alpha (n-butylaminomethyl)-2,6-bis(3-trifluoro methylphenyl) 4 pyridinecarbinol hydrochloride.-A solution of sodium borohydride (300 mg.) in water (5 ml) was added to a solution of the above bromoketone (2.2 g.) in ethanol (60 ml.) as described in Example 7. The resulting crude epoxide (1.5 g.) was dissolved in ethanol (50 ml). n-Butylamine ml.) was added and the solution refluxed for 10 hours. The reaction mixture was evaporated to dryness and the crude product converted to the hydrochloride as described in Example 7. It was crystallized from a mixture of ethanol-ether to give 750 mg. (32%) of colorless crystals, M.P. 256-258".

Analysis.--Calcd for C H Cl'F N O (percent): C, 57.86; H, 4.86; N, 5.40. Found (percent): C, 57.77; H, 4.81; N, 5.42.

Example 27.-Alpha-(2-piperidyl)-2,6-bis(4-trifluoromethylphenyl)-4-pyridinecarbinol 1) 2,6-bis-(4-trifluoromethylphenyl) 4 pyridyl 2- pyridyl ketone.-The solution of 2-bromopyridine (14.3 g., 0.08 mol) in ether ml.) was added to a solution of n-butyllithium in hexane (1.6 M, 56 ml., 0.1 mol) in anhydrous diethyl ether (120 ml.) at 70. The solution was stirred at 70 for 1 hr. after which time 2,6 di p trifiuoromethylphenylisonicotinic acid (16.5 g., 0.04 mol) was added. The solution was stirred at -60 to 70 for 2 hr. The reaction mixture was then allowed to warm to ca. -l0 and poured into ice-water (750 ml). The mixture was then extracted with ether (2 X 400 ml.). The organic layer was dried and concentrated to dryness under reduced pressure. The resulting crude solid was crystallized from isopropyl alcohol to yield the title compound (12.4 g., 66%), M.P. 143- 145.

Analysis.Calcd for C H N F O (percent): N, 5.93; F, 24.13. Found (percent): N, 5.72; F. 23.77.

(2) Alpha (2 piperidyl)-2,6-bis-(4-trifluorornethylphenyl) 4 pyridinecarbinol.Racemate A, free base: 2,6-di-(p-trifluoromethylphenyl) 4 pyridyl ketone (4.6 g., 9.6 moles) was hydrogenated over platinum .from platinum oxide (300 mg.) in ethanol (300 ml.) containing concentrated hydrochloric acid (1.1 ml.) at room temperature and 40 p.s.i. for 20 hr.; the theoretical amount of hydrogen was absorbed. The catalyst was filtered and the filtrate was concentrated to dryness under reduced pressure. The hydrochloride salt was converted to the free base by shaking with potassium hydroxide (20%) and chloroform. The organic layer was dried and concentrated. The resulting solid was slurried in diethyl ether (80 ml.) and filtered to afford a solid (1.6 g.), M.P. 168-170"; this was predominantly Racemate A by TLC (silica gel, CHC1 /MeOI-l, 6/1, R; 0.28). This material was recrystallized from isopropanol to afford pure Racemate A (1.1 g.), M.P. 168-170", one spot on TLC in the same system. The yield was 24%.

Anylsis.-Calcd for C H N F O (percent): C, 62.50; H, 4.62; N, 5.83; F, 23.72. Found (percent): C, 62.55; H, 4.75; N, 5.63; F, 23.83.

Racemate A, hydrochloride salt: Racem'ate A (1.1 g.),' free base, was slurried in hot isopropanol and isopropanol- HCl was added; the solid dissolved and crystallized slowly. The solid was collected and recrystallized from isopropanol (x1) and ethanol-water (X 1) to afiord pure Racemate A, hydrochloride salt (0.45 g.), M.P. 248-250. This product was shown by elemental analysis to be a /2 hydrate. Yield was 5 9 Analysis.--Calcd for C H N O F Cl (percent): C, 57.10; H, 4.60; N, 5.33. Found (percent): C, 56.80; H, 4.78; N, 5.27.

A sample of this salt was converted to its free base and shown to be one spot (CHCl /MeOH, 6/1, R, 0.28).

Racemate B, hydrochloride salt: The ethereal filtrate from the isolation of Racemate A was concentrated to dryness. The solid was slurried again in ether (20 ml.) and filtered to remove more Racemate A. To the filtrate was added ether-HCl. Water was then added to convert any dihydrochloride salt to the monohydrochloride salt. The ether was removed under reducer pressure and the aqueous slurry was filtered to yield a yellowish solid. The latter was slurried in ether to remove the yellow color and filtered to alford a white solid (0.5 g.). This solid was crystallized from isopropanol (X2) to afford pure Racernate B, hydrochloride salt (0.24 g.), M.P. 259-260. Elemental analysis showed the salt to be a /2 hydrate.

Analysis.-Calcd for C H N O F Cl (percent): C, 57.10; H, 4.60; N, 5.33. Found (percent): C, 57.44; H, 4.83; N, 5.28.

A sample of the hydrochloride salt was converted to its .free base for TLC purposes and was shown to be one spot (CHCl /Me0H, 6/1, R 0.36).

A mixture melting point of Racemates A and B, hydrochloride salts, was taken and the sample melted at 227- 240.

CHART 1 Alpha-( dialkylaminomethyl)-2,6-diaryl-4- pyridinecarbinols wherein one of (Ar) or (Ar) is 3 or 4-trifluoromethylphenyl and the other is X-phenyl wherein X is selected from trifiuoromethyl and monoor difinoro, chloro or bromo groups wherein X is in' the 3, 4 or 3 and 4 positions and wherein CF is in the 3 or 4 position.

13 CHART 2 Alpha- (2-piperidyl) -2,6-diaryl-4-pyridylcarbinols (Am (Ar): (Ar). -(Ar). H01

(Ar) k wherein (Ar) and (Ar) are as in Chart 1.

CHART 3 Alternative procedure for the preparation of alpha-di-nbutylaminomethyl-2,6-bis(4-trifiuoromethylphenyl) 4- pyridinecarbinol.Example 7 (also applicable to Examples 8 to inclusive) r) N/ -(Ar)i TABLE 1 P. berghei screening test (mice) B a Test method described by T. S. Osdene, P. B. Russell, and L. Bane. J. Med. Chem., 10, 431 (1967). This test has been made as a highly standardized procedure in which the P. berghei causes death of control mice at essentially 6.2 days. An increase in survival of mice by more than 2.5 days beyond this time has been found to be statistically significant. Mice which live more than 60 days are regarded as cured (0). Drugs which prolong the life of the mice beyond 14 days are considered active (A). Groups of five mice have been used at each dose level of the drugs,

b Phototoxicity determined in mice by the method of W. E. Rothe and D. P. Jacobus, J. Med. Chem., 11, 366 (1968).

a Free base.

We claim: 1. The compound of the formula:

I /R1 HooHoHN X C F;

and pharmaceutically acceptable acid addition salts thereof wherein when R is hydrogen, R is hydrogen or lower alkyl and R is lower alkyl and when R plus R is (-CH then R; is hydrogen wherein X is selected from trifluoromethyl and monoor di-fluoro, chloro or bromo groups wherein X- is in the 3, 4 or 3 and 4 positions and wherein CF; is in the 3 or 4 position.

2. The compound of claim 1 wherein X is CF;.

3. The compound of claim 1 wherein X is CF; and wherein CF; is in the 4-position.

4. The compound of claim 1 wherein X is 0P wherein CF; is in the 4-position, wherein R is hydrogen, and wherein R and R are n-butyl.

5. The compound of claim 1 wherein X is CF;, wherein CF; is in the 4-position, wherein R and R is hydrogen and wherein R is n-butyl amino.

6. The compound of claim 1 wherein X is CF;, wherein CF; is in the 4-position, wherein -R plus R is (-CH and wherein R is hydrogen.

References Cited UNITED STATES PATENT CFMCE CElll lCA'lE Cl CCREC'HCN 3,753,997 Dated August 21, 1973 Patent No.

Inventor(s) Arthur B. Ash, Peter Blumbergs, Anica Markoyac and Maurice P. LaMontagne It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, line 33 bearings should be "bearing",

Column 4, line 5'7, insert-wasbefore crystallized.

H n I Column 5, line 1, C l-l BrFNO should be C H BrF NO Column 6, line 33, Ywasher" should be "washed".

Column 6, line 3'? insert after "sal with 10% aqueous hydrochloric acid. Alter refrigerationovernight, the hydrochloric salt-- Column '7, line 19 'calcd should be --ca.lcTd-.

Column 7, line 68 "C should be --C Column 8, line 1, insert after "procedure, -described--.

Column 8, line 51 "expoxide" should be --epoxide--.

Column 8, line 61 "tartrate" should be --tartarate---.

Y? Y 7 A Column 10, line 12 C H N BrF O should be --C l1 l l BrF C--.

Column 10, 1111645, insert --Analysis--Calcd for c H 01 r N o (percent): Q 8 9}; H, 5, 60; N, 40 86.

Found: (percent) N, 41773.

)RM PO-105O (10459) USCOMM-DC 60376-P69 e u.s. GOVERNMENT PRINTING OFFICE: 1969 O366-334 UNITED STATES PATENT FFECE Page Z cERriricArE or common Pat nt 3 753,997 Dated August 21 1973 Inventor(s)ArthuI Bo Ash, Peter Blumbergs, Anica Markovac and Maurice Po LaMontagne It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 13, line 30, insert a parenthesis before "di".

Column 13, line 31, insert a parenthesis after "butylamino-methyl.

Column 14, line 14, "1. 5" should be 50 1-,

Signed and sealed'this 26th day of March 1974.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. C MARSHALL DANN Attesting Officer Commissioner of Patents- ORM PO-1050 (10-69) uscoMM-Dc 60376-P69 U.54 GOVERNMENT PRINTING OFFICE: I969 0-356-334 

